There is growing recognition that tumor vasculature plays an essential role in tumor growth. This has led to considerable interest in therapies that target tumor blood vessels. Our previous research has shown that low-intensity ultrasound identical to that used in routine physiotherapy disrupts tumor vasculature. We have also developed a sensitive ultrasound imaging assay that can be used to quantitatively monitor the antivascular action of sonication. This raises the possibility of using ultrasound to treat cancers by targeting their blood vessels. Crucial questions that are yet unanswered are whether the antivascular effects of ultrasound are reversible and what are the boundary conditions for sonication that would produce maximum antivascular effects without unwanted side effects. In this application, we propose to build on our previous research to develop antivascular ultrasound therapy for treating cancers in human patients. The proposed research has two Specific Aims. The first Specific Aim is to perform longitudinal studies investigating whether the ultrasound induced antivascular effects are permanent;and if they are not, how long do they last before the regrowth of tumor vessels begins. These studies will be conducted in a mouse melanoma model. The emphasis will be on measuring antivascular action quantitatively using contrast-enhanced power Doppler imaging. In each mouse, the sonographic findings will be correlated with tissue histology. The second Specific Aim is to perform numerical simulations to establish boundary parameters for thermal dose deposition in tumors by microbubble-enhanced ultrasound heating. The roles of microbubbles, heating rates and blood perfusion rate on ultrasound energy deposition will be studied to determine future optimal clinical sonication conditions. At the completion of this Phase 1 proposal, we anticipate having new data that we believe will be crucial for the future development of a comprehensive antivascular ultrasound device for treating cancers. Since the ultrasound intensities involved in the treatment are low and comparable to those used routinely in patients during physiotherapy treatments, a successful outcome of this project could easily be transferable to studying cancers in human patients. With the overwhelming interest in treating cancers by targeting their vasculature, the proposed research is timely and is likely to be useful in the treatment of many types of solid cancers. PUBLIC HEALTH RELEVANCE: Cancer is the second leading cause of death in the United States after heart diseases. Our previous research has led to a novel treatment for cancer using low-level ultrasound. The studies proposed in this application are designed to evaluate if the ultrasound treatment is permanent;and if it is not, how long does it take before another treatment should be given. In addition, calculations will be performed to determine the best ultrasound exposure conditions for producing the maximum ultrasound effect. The research proposed in this application would enable us to design a new ultrasound device, which while inexpensive and easy to use is effective in treating for cancers.